Patients with well-documented chronic hepatitis C are being evaluated to determine the long-term natural history and immune pathogenesis of this disease and to evaluate therapies, particularly in patients who fail to respond to conventional therapy. The current, optimal therapy for chronic hepatitis C is the combination of peginterferon (given once weekly by subcutaneous injection) and ribavirin (given orally, twice daily) for 24 to 48 weeks. This regimen induces a sustained clearance of HCV RNA from serum and improvement in serum aminotransferases and the underlying the liver disease in 50 to 60% of patients. The rate of response is highly dependent upon HCV genotype. Thus, patients with genotypes 2 and 3 (accounting for about 30% of infected patients) have a 70 to 80% response rate and can be effectively treated with peginterferon and a reduced dose of ribavirin (800 mg per day) for 24 weeks. Patients with genotype 1 (accounting for approximately 70% of infected patients in the United States), however, require treatment with full doses of peginterferon and ribavirin (1000 to 1200 mg daily) for at least 48 weeks. Furthermore, for patients who do not respond to treatment by becoming HCV RNA negative, there are few other options. Current studies in the Liver Diseases Branch, NIDDK focus on improving the safety and efficacy of current therapies and identifying treatments for patients who fail to respond to the standard therapy of hepatitis C. Thus, there are two prospective studies of viral kinetics and determinants of response to therapy with peginterferon alfa-2a and ribavirin in naive patients who have never been treated; one study for patients with genotype 1 and a second study for patients with genotypes 2 or 3. In genotype 1 patients, viral kinetic studies are done comparing the effects of peginterferon alone to those of the combination of peginterferon and ribavirin. Preliminary results indicate that ribavirin increases the second phase of viral response but the effect is minimal at 1 month. Results also indicate a rebound in viral levels between the weekly injections of peginterferon, suggesting that the dosing regimen is suboptimal. As a result of these findings, this protocol has been amended to assess twice weekly dosing of peginterferon. In genotype 2 and 3 patients, viral kinetics are done in patients who receive a reduced dose of peginterferon (90 mcg instead of 180 mcg weekly) as an attempt to decrease side effects which are considerable with peginterferon therapy. Results now indicate that the first phase of viral kinetics are suboptimal with the reduced dosages of peginterferon, and that side effects are not significantly reduced. Most importantly, the relapse rate following therapy is high and the sustained virological response rate was only 50%, which is low for patients with genotypes 2 and 3 (in whom the response rate should be 80%). For these reasons, further enrollment was stopped and new patients with chronic hepatitis C and genotypes 2 and 3 will be treated with the standard regimen of 180 mcg of peginterferon alfa-2a and ribavirin with comparison of response rates, side effects and viral kinetics to the reduced regimen. Three separate studies are underway assessing therapy of patients who fail to respond to the current optimal treatment of this disease. The first study is of long-term ribavirin monotherapy focusing on suppressing disease activity and reversing liver fibrosis. A total of 28 patients have been enrolled in this study and 10 are currently receiving ribavirin, the duration of therapy being 3 to 6 years. Follow up liver biopsies demonstrate a significant decrease in disease activity, inflammation and necrosis, but no change in fibrosis. A second study is of long-term peginterferon monotherapy of patients who fail to respond to the current optimal treatment of this disease. This study is a part of the multicenter NIDDK-funded trial known as HALT-C. The Liver Diseases Branch being one of 10 participating U.S. centers. A total of 1050 patients have been enrolled including 55 from the Liver Diseases Branch, NIDDK. Results of this study will define the role of chronic therapy with peginterferon in chronic hepatitis C and help define the natural history of hepatitis C and the role of screening for hepatocellular carcinoma in management of this disease. Analyses are now focusing upon cross-sectional analyses of the 1050 patients for issues such as determinants of disease severity, biomarkers for fibrosis and liver cancer and quality of life. A third study of non-responder patients is now completed and focused on use of gamma interferon, a T cell cytokine that has antiviral activity against HCV in the replicon tissue culture system. Eleven patients who failed to respond to combination therapy were treated with a 4-week course of three different doses of gamma interferon while being monitored for changes in HCV viral levels. HCV RNA levels did not change at any time during therapy with any of the three doses. Serum aminotransferases were also unchanged. Finally, the Liver Diseases Branch participates in long-term natural history and immunological studies of chronic hepatitis C in collaboration with the Division of Transfusion Medicine. Volunteer blood donors found to have chronic hepatitis C are followed at regular intervals and undergo liver biopsy at 5 year intervals. Recent analysis have focused on predictors of disease progression. These studies will help define the natural history of hepatitis C and the clinical correlates that predict disease progression.